The goals of the CSGADP program are to understand the immune mechanisms that underlie autoimmune disease and the consequences of manipulation of the immune response in autoimmunity in order to apply this information to the prevention of autoimmunity in humans. This grant application addresses these goals with respect to understanding the mechanisms that regulate the fate and function of CD4 effector T cells and Treg. Specifically we address how alterations in the IL-2/STAT5 and IL-6/STAT3 cytokine signaling pathways contribute to the loss of this balance in individuals with T1D, MS and CD. These two pathways are known to have opposing influences on the function and development of Treg, and the development of potentially pathogenic CD4 effector cells. Genetic variants link the IL-2R/STAT5 pathway to T1D, MS and IBD, and the IL- 6/STAT3 pathway to MS and CD. In this grant, we pose the hypothesis that in autoimmune individuals enhanced phosphorylation of STAT3 and diminished phosphorylation of STAT5 establish a functional program biasing cytokine responses towards a skewed, pro-autoimmune profile. We will test this hypothesis by determining the extent to which signaling via STAT5 and STAT3 is altered in three autoimmune diseases; type 1 diabetes (T1D), multiple sclerosis (MS) and Crohn's Disease (CD). We will determine whether these alterations in phosphorylation, independently and in combination, lead to an imbalance between Treg and Th17 cells and/or enhance the resistance of effector T cells (Teff) to suppression. We will then determine the molecular mechanisms that lead to these alterations, using disease-associated genetic polymorphism as a guidepost. Aim 1. We will address the hypothesis that blunted STAT5 signaling in response to IL-2 results in a diminished induction, function and stability of Treg in T1D, CD and MS. We will examine this question in the context of blood and then extend these studies to the tissue in the setting of CD. We will then determine the biochemical and genetic mechanisms that lead to the defect in IL-2R signaling in each disease. Aim 2. We will address the hypothesis that enhanced phosphorylation of STAT3 in response to IL-6 leads to the development and persistence of pathogenic T cells in autoimmunity, by promoting the expression of ROR?t, restraining expression of FOXP3 and enhancing the resistance of effector T cells to suppression by Treg. We will examine this question using genotyped controls to address molecular mechanism and T1D, MS and CD patients to address disease phenotypes. Aim 3. We will test the hypothesis that enhanced phosphorylation of STAT3 and diminished phosphorylation of STAT5 in combination reverse the balance of Treg and Teff functional profiles upon antigen challenge.